Use of E-cigarette (ECs) devices has increased dramatically over recent years. Newly developed high-output ECs have the potential to delivery a variety of highly addictive drugs in addition to nicotine. Since inhalation produces nearly instantaneous CNS access it raises the alarming possibility that both opioid and psychomotor stimulant abuse by vaping may become serious public health concerns. However, at this time little is known about the reinforcing effects of drugs, other than nicotine, delivered using ECs and appropriate animal models are lacking. The present proposal seeks to fill this vacuum using a newly developed rodent vapor-puff delivery self-administration system to assess the reinforcing effects of fentanyl (FEN) and methamphetamine (METH) vapor. We will utilize the well-established fading principle to engender self-administration of FEN or METH vapor in separate groups of male and female rats. Rats will initially be trained in daily 1-hr operant sessions to emit lever responses in order to activate a nose poke device for delivery of a sweetened milk solution. The dipper cup delivering the milk will be elevated into the vapor delivery aperture thereby bringing the rat's nose into contact with vapor puffs. Over successive daily training sessions, 3 sec exposures to increasing concentrations of FEN or METH in e-juice vapor (50% vegetable glycerol/49% propylene glycol/1% yellow cake flavor) will occur concurrently with milk reinforcer presentation. Once behavior for the combination of the liquid reinforcer and vaped FEN or METH has reached stable, behaviorally-active levels we will discontinue the paired administration of milk reinforcers through a gradual daily fading procedure until responding is maintained by only FEN or METH vapor delivery. After vapor self-administration is established we will install an additional vaporizer activated by the lever-presses on a second lever permitting the use of a choice paradigm to examine the reinforcing effects of a range of FEN or METH concentrations. During dose-effect curve testing, responses on one lever of the operant chamber, signaled by a solidly illuminated lever-light, will occasion the opportunity to engage in nose-pokes that deliver drug-laden vapor whereas nose pokes following a response on the opposite lever, signaled by a blinking lever-light, will deliver drug-free vapor acting as a control that is identical in all respects aside from the presence of drug. As a second complimentary method of assessing the reinforcing effects of FEN or METH vapor we will utilize a progressive ratio test procedure. In addition to varying drug concentration we will parametrically explore the role of vaporizer output wattage in modulating the reinforcing effects of drug vapor. Lastly, commercial e-juice is composed of flavors, vegetable glycerol (VG) and propylene glycol (PG). The addition of flavor may play an important role in promoting and maintaining self-administration. To test this hypothesis we will systematically vary e-juice concentrations of flavor additive to examine the extent to which it impacts the reinforcing effects of FEN or METH vapor.